The present invention, in some embodiments, relates to the field of therapeutics, and more specifically to Klotho variant polypeptides, polynucleotides encoding same, and the use thereof in therapy, especially for the treatment of cancer.
Klotho protein is a single-pass transmembrane protein.
Human Klotho protein (SEQ ID NO:1) is 1012 amino acid residues long while murine Klotho protein (SEQ ID NO:81) is 1014 amino acid residues long. All alignment programs confirm a shift of 2 amino acids between the human (1012 amino acids) and mouse (1014 amino acids) Klotho polypeptide sequences. For example, Glu414 in human Klotho protein is the equivalent of Glu416 in mouse Klotho protein and Asp238 in human Klotho protein is Asp240 in mouse Klotho protein.
Klotho protein has been implicated in a number of biological activities including forming a complex with Fibroblast Growth Factor (FGF) receptors and functioning as an obligate co-receptor for FGF23, a bone-derived hormone that induces phosphate excretion into urine. Mice lacking Klotho or FGF23 not only exhibit phosphate retention but also display a premature-aging syndrome, revealing an unexpected link between phosphate metabolism and aging.
Secreted Klotho has been implicated in a number of biological activities including a humoral factor that regulates activity of multiple glycoproteins on the cell surface, including ion channels and growth factor receptors such as Insulin/Insulin-Like Growth Factor-1 receptors.
In US 2010/0330062, the Inventors disclosed that Klotho protein and related compounds have anti-cancer properties and also disclosed the use of Klotho protein and related compounds in the treatment of cancer.